Activation of renal mechanosensory nerves increases afferent renal nerve activity (ARNA) resulting in decreases in efferent renal sympathetic nerve activity (ERSNA) and natriuresis, a renorenal reflex. Increases in ERSNA increase ARNA which, in turn, exerts a negative feedback control of ERSNA via activation of the renorenal reflexes. Activation of renal sensory nerves is enhanced by high sodium (HNa) and reduced by low sodium (LNa) diet;the modulatory action of dietary Na is mediated by changes in angiotensin (ANG) II. Selective afferent renal denervation results in salt sensitive hypertension, suggesting an important role for the natriuretic renorenal reflexes in regulation of sodium balance and arterial pressure. The renorenal reflexes are impaired in congestive heart failure (CHF) and hypertension due to increased endogenous ANG II suppressing renal sensory nerve activation. Endothelin-1 (ET-1) plays a differential role in the activation of renal sensory nerves, stimulatory in HNa diet via activation of ETB-receptors (R) and inhibitory in LNa diet via activation of ETA-R. Activation of ETA-R contributes the ANG ll-induced suppression of ARNA. OBJECTIVES: To examine the role of ET-1 in the control of ERSNA and maintenance of sodium balance and define the mechanisms involved in the ET-1 mediated modulation of ARNA. SPECIFIC AIMS: Determine whether (1) the renorenal reflexes are impaired in ETB-R deficient rats and (2) the expression of ET-R in the renal pelvic wall and dorsal root ganglia is altered by dietary sodium. Define (3) the mechanisms involved in the activation of ETB-R and ETA-R in the stimulation of the afferent renal nerves;(4) the role of ET-1 in the impaired renorenal reflexes in pathological conditions of increased ANG II (CHF) and (5) the mechanisms involved in the interaction between ERSNA and ARNA at the level of the peripheral renal sensory nerve endings. METHODS: Afferent renal nerves will be stimulated by increasing renal pelvic pressure or reflex induced increases in ERSNA. ARNA and ERSNA will be recorded. Renal pelvic release of substance P, PGE2, and norepinephrine will be measured by ELISA/RIA. ETA-R and ETB-R will be localized and quantified in renal pelvis by real time RT-PCR, western blotting, in situ hybridization and immuno- histochemistry. Understanding the mechanisms involved in the ET-1-mediated activation of renal sensory nerves may further our understanding of the role of ET-1 in sodium balance, heart failure and hypertension.